Efficacy of rFIXFc versus N9-GP Prophylaxis in Patients with Hemophilia B: Matching-Adjusted Indirect Comparison of B-LONG and PARADIGM 2 Trials

Maria Elisa Mancuso; Daniel Eriksson; Aletta Falk; Zalmai Hakimi; Piotr Wojciechowski; Marlena Wdowiak; Robert Klamroth

doi:10.2147/JBM.S389094

Efficacy of rFIXFc versus N9-GP Prophylaxis in Patients with Hemophilia B: Matching-Adjusted Indirect Comparison of B-LONG and PARADIGM 2 Trials

J Blood Med. 2023 Jul 27:14:427-434. doi: 10.2147/JBM.S389094. eCollection 2023.

Authors

Maria Elisa Mancuso^{1

2}, Daniel Eriksson³, Aletta Falk³, Zalmai Hakimi³, Piotr Wojciechowski^{4

5}, Marlena Wdowiak⁴, Robert Klamroth^{6

7}

Affiliations

¹ Center for Thrombosis and Hemorrhagic Diseases, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.
² Humanitas University, Pieve Emanuele, Milan, Italy.
³ Swedish Orphan Biovitrum AB, Stockholm, Sweden.
⁴ Creativ-Ceutical, Krakow, Poland.
⁵ Assignity, Krakow, Poland.
⁶ Department of Internal Medicine, Hemophilia Treatment Center, Vivantes Klinikum im Friedrichshain, Berlin, Germany.
⁷ Institute of Experimental Hematology and Transfusion Medicine, University Hospital Bonn, Medical Faculty, University of Bonn, Bonn, Germany.

Abstract

Purpose: For patients with hemophilia B, extended half-life factor IX (FIX) products are available for prophylaxis and for treating bleeds. Different methods are used to extend the half-lives of recombinant FIX Fc fusion protein (rFIXFc) and nonacog beta pegol (N9-GP). This affects their biodistribution and plasma FIX levels, although differences do not always correlate with clinical outcomes. A matching-adjusted indirect comparison (MAIC) of prophylaxis with rFIXFc and N9-GP was performed, based on licensed dosing in the European Union.

Patients and methods: Combined rFIXFc data from the weekly and individualized interval prophylaxis arms of the B-LONG clinical trial, and N9-GP data from the 40 IU/kg once-weekly prophylaxis arm of PARADIGM 2 were used in a MAIC. Individual patient data for rFIXFc (n=87) were matched to aggregated data for N9-GP (n=29). Estimated annualized bleeding rates (ABRs) for rFIXFc were recalculated using a Poisson regression model with adjustment for over-dispersion, and compared with ABRs reported for N9-GP, using incidence rate ratios (IRRs) with 95% confidence interval (CI).

Results: There was no evidence of significant differences in estimated ABRs between prophylaxis with rFIXFc and N9-GP. Analysis of pooled rFIXFc weekly and interval-adjusted dosing compared with N9-GP 40 IU/kg once weekly produced estimated ABRs of 2.59 versus 2.51 (IRR 1.03; 95% CI 0.56-1.89), as well as 1.34 versus 1.22 (IRR 1.10; 95% CI 0.42-2.91) and 1.13 versus 1.29 (IRR 0.88; 95% CI 0.47-1.63) for overall, spontaneous, and traumatic bleeding events, respectively.

Conclusion: The study did not reveal any significant differences in the efficacy of rFIXFc and N9-GP prophylaxis. Given differences in trough levels (rFIXFc dosing was targeted to achieve a trough 1-3 IU/dL above baseline versus a reported estimated N9-GP mean trough of 27.3 IU/dL), interpreting plasma FIX levels as potential surrogate efficacy markers requires consideration of compound-specific pharmacokinetic profiles.

Keywords: annualized bleeding rate; factor IX Fc fusion protein; factor IX deficiency; nonacog beta pegol; plasma factor IX activity; treatment outcome.